Saturday, October 27, 2012

I am in the midst of a new academic year of talks. Last week I went to the Brigham and Women's Hospital behavioral neurology interest group talk, and last Thursday to Boston University Medical Center Psychiatry Grand Rounds. I do like these academic talks, though naturally the audience is much more skeptical than the Ancestral Health Symposium and PaleoFx folks. Skepticism is good. Keeps me on my toes. At the Brigham Behavioral Neurology group, I had immediate questions involving how long our ancestors lived, how old was the individual who owned the beautiful choppers in the ancient Maori skull when he/she died, and what exactly were the questions asked by Staffan Lindeberg and company to determine that the Kitavan elders didn't seem to have symptoms of dementia.

All important questions! I didn't have answers to as many as I wanted to… but I think I held my own. I do try to make the point that my blog is not about answers, but rather about asking these questions for research in a meaningful way. If the government food plate leads us to "whole grain" sugary honey nut "O" cereal as a big healthy part of our diet, and beautiful nutrient-rich egg yolks are deadly, maybe we should step back and think about that for a moment.

Grand Rounds at Boston Medical Center went well. I thought the talk was received with interest, and I certainly thank Dr. Searl and Dr. Chapman for inviting me to speak. I hope that someone thinks about a research idea…I'm particularly hopeful that we will get more research about fructose malabsorption and depression. We'll see.

The textbook has quite a bit to say about mental illness, a whole chapter (pages 189-220), which is quite amazing, as most anthropology and hygiene hypothesis tends to avoid mental illness. So much easier to focus on diabetes and obesity and autoimmune disease. All easily marked and tallied. Not so mental illness, defined by the recipe book of symptoms we call the DSMIVTR.

Well. Stress-related psychiatric disorders (which is nearly all of them, when I think about it), particularly depressive and anxiety disorders, are associated with markers of inflammation, particularly raised levels of proinflammatory cytokines. Some of the proinflammatory cytokines (most famously interferon alpha, used to treat hepatitis C) can induce depression in folks with no previous symptoms. Thus it is reasonable to assume that immune dysregulation, that is our immune system a bit out of whack, like an army milling about without clear leadership, could be part of mental illness.

Like autoimmune disease and allergic disorders (athma, hay fever, type I diabetes, multiple sclerosis, and inflammatory bowel diseases such as ulcerative colitis) have been increasing preciptiously in the developed world in recent decades. The "old friends hypothesis" suggests that we are, in effect, missing a major regulator of our immune system that we co-evolved with for thousands upon thousands of generations. That is, three classes of organisms who have lived within us or passed through us, all of our ancestors, until very recently. They are the pseudocommensals, the commensals, and the parasitic worms. (More about the old friends hypothesis in this article.)

The down and dirty of it is that we have several arms of our immune system, kind of like infantry and navy and military intelligence. There are various forms of T helper cells (Th1 and Th2) that secrete inflammatory cytokines to tell which arms of our immune system to come forth and attack. What will tell the Th1 and Th2 cells to back off is a third variety of T cell, called Tregs (short for regulatory T cells). Infection with our "old friends" (such as pinworms, or tapeworms, or the pseudocommensals like soil mycobacteria) seems to cause continuous activation of the Tregs, keeping the Th1 and Th2 cells in check. In effect, these "old friends" organisms have always been there, and have become a part of our immune system. It is no wonder that we have problems when we no longer have the old friends at our disposal.*

Both Th1 and Th2-regulated inflammation have been associated with anxiety and depression. The "pro-inflammatory cytokines" IL-1, IL-2, IL-6, IL-12, TNFalpha, and interferon alpha and gamma. On the Th1 side, IL-6 and IL-1 levels are related to symptoms of depression in cancer patients and others. Downstream agents, such as C reactive protein, cerulosplasmin, and lower levels of zinc and albumin are also associated with depression symptoms. There are also increased levels of neutrophils and complement proteins** seen in acute exacerbations of bipolar disorder and major depressive disorder. Seems that people with increased levels of background inflammation are more susceptible to interferon and IL-2 administration causing depressive symptoms as well.

When we go over to the Th2 side of things (Th2 excess seems to be associated with allergies and hay fever and ulcerative colitis, whereas Th1 excess is associated with other autoimmune diseases such as type I diabetes and crohns), the evidence for specific cytokines is not as clear. However, people with allergies are known to have a greater incidence of depression. 50% of asthma sufferers seem to have clinically significant depression, and allergies are associated with an increased risk of suicide. Asthma is also clearly associated with anxiety (in studies, and also any experienced clinician can tell you… trouble breathing causes great anxiety and worries about future attacks). However, that association begs an important question…is it the immune dysregulation causing both anxiety and asthma, or the asthma symptoms particularly prone to causing anxiety? Until we have a better handle on the Th2 cytokines such as Il-4 (experimental tests are problematic) we may not know.

So, there is an enzyme called IDO, which can act on tryptophan leading to a depletion of serotonin. Inflammation seems to activate IDO, whereas antidepressants (such as SSRIs) seem to deactivate it, which may be the secret to how they might work. In pregnancy, there is a bias toward Th2 and regulatory T cells (thought to prevent immune attack on the growing fetus. Mothers-to-be are in a somewhat immune compromised state, particularly in the third trimester, which can actually decrease the incidence of some autoimmune symptoms during pregnancy). After pregnancy, however, there seem to be a Th1 "bounce back" that can lead to exacerbation of inflammatory disorders and depression. There is increased metabolism of tryptophan and increases in Th1-related cytokines.

What about the gut and depression? Are raised levels of immune cytokines seen in depression caused by "leaky gut"? Levels of antibodies directed against several gut bacterial species are elevated in people with depression, suggesting leakiness. Leakiness is associated with increased bacterial endotoxin crossing the gut barrier, leading to increases in proinflammatory cytokines, which could plausibly cause depression symptoms. Gut epithelial barrier permeability is highly dependent upon the enteric immune system, and parasites and healthy, normal commensal organisms may help regulate and protect normal gut integrity. It's not a coincidence that Chron's and ulcerative colitis are associated with higher levels of affective disorders.

Depression is also very common in folks with vascular disease (those at high risk for heart attacks and thrombotic strokes). Metabolic syndrome, associated with athersclerosis and heart disease, is also associated with depressive symptoms. Brain-derived neurotrophic factor (a nerve fertilizer of sorts) seems to be diminished in depression and in vascular disease. Levels of BDNF are low before treatment, and seem to rise in response to succesful treatment. Autoimmune diseases such as MS are also noted for low levels of BDNF.

There are a lot of intriguing connections between whole-body immune pathology and depression and anxiety symptoms. Gut and immune dysregulation may be keys to these disorders. It will take more time and more asking the correct questions to find out whether these issues are of fundamental importance or not. Psychiatrists might want to read up on the immune system, however, as a part of continuing medical education.

*there are clear benefits to a hygenic water supply (unless you like cholera for breakfast), not eating dirt, and not having unchecked parasitic infections. Don't go drink untreated pondwater after reading this post. But my guess is that better study of these organisms will lead to safe and ingenious ways to emulate the old friends with much less risk than drinking untreated water and living with hookworms.

** a thorough grounding in immunology is beyond the scope of my post. However, these wikepedia articles can give you a good start.

Thursday, October 18, 2012

"Fake it until you make it." This phrase, though often met with derision, constitutes some practical advice when dealing with a devastating problem like chronic depression.

There are, at the base of it, two major psychotherapeutic approaches to the treatment of depression. One way to explore relationships and history to find past trauma and metabolize it in order to get through it and better under stand current pain. Another approach is to focus on appropriate lifestyle and coping habits to reduce depression. The phrase "fake it until you make it" speaks to the second "cognitive behavioral" method.* One extreme (but interesting) version of behavioral therapy is called "solutions based" therapy. I learned about it in residency and dabbled a bit with the ideas in practice, but saw it popularized most recently in the scorching (but intolerably paced, plotted, and characterized) "50 Shades" trilogy. Solutions based therapy apparently helped the billionaire hero, but not enough so he could give up his sex dungeon. It takes a co-ed implausibly promoted to senior book editor to do that.

In any event, solutions-based therapy begins with the "miracle question." Let's say in the middle of the night while you were asleep, a miracle happened and you were cured of depression. How do you know you were cured? What do you feel when you wake up in the morning that is different? How is your energy? What does your face look like when you first see yourself in the mirror? How would your loved ones know you are cured and what would they see? The idea is to focus on those "solutions." If being happy means having energy in the morning and looking at yourself in the mirror and seeing bright smile, then maybe changing some habits so your sleep improves and grinning at yourself in the mirror can be part of the cure.

Believe it or not, there is some research to suggest that treatment with botox, paralyzing certain muscles to prevent deep scowling, can be an effective antidepressant treatment as well. And no, this treatment is not exactly "evolutionary psychiatry" but I do like to explore novel ways to look at the pathology and treatment of mental illness, and I would say the cosmetic cure qualifies. Even looking at smiling faces makes people happier. Do you think our ancient ancestors were more carefree than we are? More relaxed? More apt to smile? I wish I knew the answer to that question. It's not preserved in the fossil record.

The largest and perhaps most famous trial of resistant depression patients was the STAR*D trial (and I did have the privilege of sitting in on some of the weekly research meetings at MGH while this trials were being conducted). "Resistant" depression means depression that lingers despite antidepressant treatment. Only 30% of these patients find significant relief from the medication antidepressants that are available, of whatever variety. Nearly 50% of medicated patients discontinue antidepressants within 6 months, though most data suggests that treatment of 9-12 months after remission is most effective.

Other new technologies, such as inserted vagus nerve stimulation (VNS) devices and transcranial magnetic stimulation (TMS) have tried to fill the void in resistant depression treatment. They remain out of reach for most patients as insurance will generally not pay for them. The other treatment for severe resistant depression is electroshock therapy, which tends to be quite effective but has many side effects and can be very disruptive. In truth, the data for resistant depression for most modalities is poor. Not much we've discovered so far will work well, and drug companies don't want to spend millions on a trial that will likely result in failure. To find a new experimental method used in resistant patients is actually rather exciting.

(Lest we get too excited) the study I'm reviewing is merely a pilot trial. 30 people with resistant depression (average duration of 16 years) were randomly assigned to botox injection or saline placebo injection (and by the end 90% of people were able to tell whether or not they got the active agent, which pretty much negates the blinding). The single injection was made into the glabellar region (right at the top of the nose, where forehead scowling lines will center). To try to preserve a bit of experimental blinding at least for the raters for the follow ups, everyone wore a skullcap to cover the forehead. Scale ratings were done via the rather classic Hamilton D 17 item depression scale. Inclusion into the trial involved full structured clinical interview with a diagnosis of major depressive disorder, which is gold standard. Response to treatment was tracked from week 2 to 16 weeks after the injection.

HAM-D scores improved a whopping 10.1 points in the treatment group in 6 weeks versus 1.7 in the control group. Nonresponse is characterized as a <25% reduction, partial response a 25-50% reduction, and >50% reduction in HAM-D score is considered "remission" and the holy grail of psychiatry in resistant depression treatment. In this trial, partial response in the treatment group was 86.7% vs. 26.7% of the placebo. That's a pretty big deal in resistant depression. Actual depression remission occured in 33.3% of active treatment vs. 13.3% of placebo which was not statistically significant given the small sample size. Let me put it thusly:

In this little study, a single botox injection was a bit better than the classic antidepressants and really blows the expensive and/or invasive TMS or VNS treatments out of the water. The only side effect reported was a mild short-term headache. Antidepressants tend to cause sexual dysfunction and/or weight gain or stomach upset or sweating or a number of other issues, and botox needs to be repeated only every 4 months or so, rather than daily pills.

There are a lot of limitations in this study. It was small. Mostly women. Mostly the melancholic subtype of resistant depression (which can actually be easier to treat). Most of the patients guessed correctly whether they were in the treatment group or not, so blinding was a huge issue. But the theory is that the more positive facial expressions after botox treatment deliver positive neurofeedback, improving mood, and causing the treatment effect.

But, as a psychiatrist, the most exciting procedure I tend to perform on patients is checking blood pressure. It might be nice to inject some botox now and again. I'm a terrible evolutionary psychiatrist, when it comes down to it.

*In actuality, most therapists in practice combine the two methods, and a manualized and studied version of that is called short-term dynamic psychotherapy, the textbook of which was written by one of my teachers in residency, Leigh McCullough, PhD. I was saddened to learn she died of ALS earlier this year.

Bam. I'm getting all Emeril about it because finally we are getting some thoughtful and complete studies. We're talking measuring the plasma membrane ratios of omega 3 to omega 6, supplementing, measuring again, and measuring inflammatory markers as well as response to supplementation. These studies are not phoned in by the statisticians after they whip up another algorithm on the supercomputer over at HSPH.*

Here we have a small randomized placebo-controlled trial of 22 elderly (66-95 y/o) depressed females given omega 3 supplementation (2.5 grams daily of an EPA/DHA 2:1 mix for 8 weeks) and 24 given a placebo (parrafin oil, lemon flavored, just like the other--known for being insoluble in water, poorly absorbed, and flammable). Not only were pre and post depression scales measured, but so were plasma membrane omega 6/3 ratios (measured as AA/EPA in HUMAN SUBJECTS, Chris Barrera), and lots of inflammatory markers (notably CD2, CD3, CD4, CD8, CD16, CD19 and the cytokines IL-5 and IL-15. What, no IL-6 and TNFa? Little evolutionary psychiatry joke**). (But it is important to remember that depression is associated with T cell dysfunction, particularly the regulatory T cells that but the kibosh on inflammation).

The paper proper begins with a rather awkward but correct statement: "An unbalance in polyunsaturated fatty acid (PUFA) status is observed in various pathological conditions, especially in chronic and/or degenerative diseases associated with antioxidant system deficiency."Low DHA in the central nervous system has been associated with all sorts of badness, such as depression, anxiety, ADHD, and dementia. The elderly seem to be particularly at risk, because their ability to change other forms of omega 3 to the long chain forms needed in the CNS is decreased compared to younger folks. (Less delta6 desaturase activity.)Results!Rachmaninov (Vocalise for Violin).
After 8 weeks, only the intervention group with the omega 3 had a significant decrease in the Geriatric Depression Scale scores. AA/EPA ratio were significantly higher in depressed patients than in healthy ones (from another group of healthy, non-depressed elderly women who were not taking omega3 supplementation). Not surprisingly, the AA/EPA ratio decreased significantly in those taking the omega 3 supplement in the depression group, which correlated with the decreased depression scores. Ratios did not change in the placebo group or in the "healthy" group.

Inflammatory markers were significantly correlated with being depressed at the beginning of the study (not exactly a newsflash) but were not correlated at the end of the study, though there were some shifts in markers. Hey, it was only 8 weeks.

I like this study a lot, for several reasons. They used an omega 3 supplement with EPA greater than DHA, which are the only sorts of supplements shown to be effective in depression. They used an inert placebo (coconut oil is another acceptable substitute) in lieu of olive oil or (gasp) omega6 oil. They measured plasma ratios, depression scores, and inflammation.

I also learned something very interesting that I didn't know before, which is that mood stabilizers, particularly lithium, have been associated with greater AA turnover and increased DHA in the plasma membranes in the frontal cortex. One more mechanism whereby lithium is an essential micro nutrient? Maybe. One more reason to consider that we don't fully understand nutrition or the brain but we should probably take in a reasonable amount of these? Yes.

*There is something to be said for supercomputers and 100,000 person data sets. But I'm not going to eat corn oil and kashi.

** from the study "numerous studies have indicated major depression as an inflammatory state with elevated levels of proinflammatory cytokines, e.g. Interleukin IL-6, IL-12, interferon (IFN)-γ [15], IL-1 and tumor necrosis factor (TNF)-α [16]. For this reason we decided to evaluate cytokines that have not yet been sufficiently studied to date, such as IL-5 and IL-15, in this study."

Monday, October 8, 2012

Researching the viability of ketogenic diets for therapeutic usage was one of the original interests that launched this blog. And while there is growing data for brain cancers and even a Cochran review for the use of ketogenic diets in epilepsy, the bipolar story has always been theoretical.

Ketogenic (very low carbohydrate and low protein) diets should work a bit like the mood stabilizer depakote in regulating unstable moods in bipolar disorder, making them an interesting option, should the research pan out. I explore the research and details in this post:

But, as I stated in that article, there were no randomized controlled trials, not even a pilot trial, and the only two case studies I had unearthed had one guy getting psychotic on Atkins induction and another one where a hospitalized bipolar woman showed no benefit (but despite reported enthusiasm and being in an inpatient unit where her food was supposedly entirely controlled, she never acheived ketosis).

And here we have not one, but two rather well documented cases of bipolar II disorder in women, beginning in youth with some hypomania, in one person predictable seasonal depressions in the summer and a bit of mania in the spring. Both women had bad responses (such as suicide attempts and suicidal thoughts) to antidepressant trials and one gained weight on quetiapine. They were tried on lamotrigine, an anticonvulsant and mood stablizer, with okay results (one woman was finally able to maintain a job and be functional). One tried a ketogenic diet to help with some irritable bowel symptoms, the other just wanted to try the diet. One woman ate raw cream, grassfed beef, organic pork, free range chicken, and seafood. The other ate mostly chicken, fish, and coconut oil with 2-3 cups of vegetables a day. Both monitored their urine with ketostix or Ketone Care Test Strips most days for several months, achieving mild to moderate ketosis on most days. Both women eventually discontinued the lamotrigine and reported better symptom control with the diet than with medication.

One woman described her irritability going away and a sense of calm. Also "having my head screwed on straight--well, it's definitely worth giving up pie." She said her symptoms seemed better with a ketone level of 15mg/dl vs 5 mg/dl in the urine. The other woman noted that if she remained gluten-free, she felt much better, even though she had never been diagnosed with celiac disease.

Neither woman had any adverse consequences and they remained stable on the diet for 2-3 years at the time the paper was published.

The paper details how a slight acidosis achieved with a ketogenic diet results in decreased intracellular sodium accumulation, which is the mechanism by which all anticonvulsants which are also mood stabilizers appear to work. In addition, the paper details some possible pitfalls of a ketogenic diet, such as difficulty maintaining it in a world of twinkies and coca-cola, and the risk of kidney stones. The author recommends >2.5 liters a day of fluids and a potassium citrate supplement to alkinilize the urine, which is done routinely in pediatric clinics where ketogenic diets are used for seizures, but may not be be necessary in adults. There is a long-term review of the ketogenic diets in kids (though I'm not a fan of the ingredients in some of the formulas used for tube-feeding some of these kids - soybean oil, soybean oil and more soybean oil) talking about complications over 6 years. Since these kids were often very ill with many other debilitating conditions, it is hard to attribute the complications (sepsis, cardiomyopathy, lipid pneumonia) to the diet itself.

Lipids were measured in one woman from a vegetarian to an omnivorous to a ketogenic diet. As is expected her trigs dropped and her LDL and HDL went up on the ketogenic diet. Total cholesterol to HDL ratio (the best cheap test I know of relating to total LDL particle number, with a lower ratio being better) on the vegetarian diet was 4.47, 3.78 on the omnivorous diet, and 3.74 on the ketogenic diet.

All in all, the paper is a nice illustration of two motivated patients acheiving remission of their bipolar symptoms (which they had dealt with for decades) with a free-living ketogenic diet (and some other supplements, though each woman took different ones, for example, probiotics and omega 3). Two anecdotes isn't a huge amount of data, but it is intriguing, and I would say the time for a randomized controlled trial of ketogenic diets in bipolar disorder is way overdue.

(Final note as I was in a bit of a hurry when I wrote the post at first… I did want to say there is a *lot* about these case study diets that could be therapeutic. No processed food, no sugar, lots of nutrients, lots of omega 3, low in gluten or gluten-free, likely low in histamine. The tracking of the ketones and one women's experience that the 15mg/dl ketone level felt more calming to her along with the sensible biologic mechanism makes the ketosis part plausible, but it is important to note these other possible factors).

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About Me

Emily Deans, M.D.: I'm a psychiatrist in Massachusetts searching for evolutionary solutions to the general and mental health problems of the 21st century. Disclaimer: This information is for educational purposes only, and is in no way intended to be personal medical advice. Please ask your physician about any health guidelines seen in this blog, as everyone is different in his or her medical needs.